tbuckley/cabot-search huggingface dataset:
Abstract WS2-3: Therapy-induced senescence: Friend or foe?
Authors: Sheila Stewart
Journal: Cancer Research (2023)

Abstract The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKa is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using clinically relevant breast cancer metastasis models, we show that orally administered, small-molecule inhibitors of p38MAPKa or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we found that this effect is mediated by inhibition of the p38MAPKa pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also found that these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impacts their quality of life. Mechanistic studies revealed that p38MAPKa’s ability to limit tumor growth within the bone is dependent on CD4 T cells and macrophages. To determine which cell types within the bone contribute to tumor growth and bone loss, we carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We found numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKa or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Citation Format: Sheila Stewart. Therapy-induced senescence: Friend or foe? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-3.
Abstract P6-04-04: Clinical Relevance of PD-L1 and CD8 Expression in Triple Negative Breast Cancer
Authors: Zsuzsanna Bago-Horvath, Maximilian Marhold, Ulrike Heber, Rupert Bartsch, Florian Fitzal, Christian F. Singer, Martin Filipits
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibitors such as PD-L1 are promising therapy targets in triple negative breast cancer (TNBC). In the present study, we examined the clinical relevance of PD-L1 and CD8 expression in TNBC patients treated with adjuvant chemotherapy. Methods: FFPE tumor material from 118 patients with early TNBC treated between 1999 and 2012 was included in our analysis. Immunohistochemical (IHC) expression of PD-L1 was determined by immune score using the diagnostic antibody SP142 (Ventana). CD8 IHC was performed using the SP57 antibody (Ventana). Follow-up data were available for all 118 patients with a median follow up time of 19.4 years. Biomarkers were examined as continuous or categorical variable (predefined cutoffs). Invasive disease-free survival (IDFS) and overall survival (OS) were analyzed using Cox regression models. Results: The median PD-L1 immune score was 1% and PD-L1 expression was classified as positive in 79/116 (68.1%, cutoff ≥1%) cases. Median CD8 expression was 10% and was scored as positive in 51/115 (44.3%, cutoff &amp;gt;10%) samples. Significant associations were observed between PD-L1 expression and tumor grade, Ki67, and CD8 expression. PD-L1-positive tumors were more frequently in the G3 group (p=0.006) and had higher Ki67 (p&amp;lt; 0.001) and higher CD8 expression (p&amp;lt; 0.001). PD-L1 but not CD8 expression was associated with IDFS or OS. Univariate Cox regression analyses showed that PD-L1-negative patients had a shorter IDFS (HR 0.52, 95%CI 0.30-0.89, p=0.02) and showed a trend towards shorter OS (HR 0.56, 95%CI 0.30-1.03, p=0.06). CD8 expression was neither associated with IDFS (HR 0.74, 95%CI 0.43-1.27, p=0.27) nor with OS (HR 0.87, 95%CI 0.48-1.60, p=0.66). In multivariate analyses, PD-L1 expression was an independent prognostic factor for IDFS (HR 0.51, 95%CI 0.29-0.88, p=0.016) but not for OS (HR 0.53, 95%CI 0.28-1.01, p=0.052). Conclusions: Our results suggest that PD-L1 but not CD8 expression assessed by IHC predicted outcome in TNBC. Further analysis of larger, suitable patient cohorts is warranted to further assess the prognostic and predictive value of PD-L1 expression. Citation Format: Zsuzsanna Bago-Horvath, Maximilian Marhold, Ulrike Heber, Rupert Bartsch, Florian Fitzal, Christian F. Singer, Martin Filipits. Clinical Relevance of PD-L1 and CD8 Expression in Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-04-04.
Abstract P3-07-01: Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe
Authors: Ying Yan, Janina Baranowska-Kortylewicz, Brendan Graff
Journal: Cancer Research (2023)

Abstract Metastatic breast cancer (mBC) is still an incurable disease and is responsible for the majority of breast cancer-related death, despite tremendous efforts spent on developing better regimens for mBC. Microtubule-targeting chemotherapy agents (MTAs) have been on the front lines of treating mBC. However, many of these drugs become ineffective following treatment, as a consequence of either primary or acquired resistance, which leads to refractory disease. Furthermore, failures of the first-line MTA treatment will negatively affect the effectiveness of the second- and third-line agents in the patients, as the overall response rates of the subsequent treatments are in a range of only ~12% to 35%. Thus, there is an urgent need for alternative MTAs that are significantly different in biological characteristics from those currently used MTAs for mBC therapy. For this purpose, we investigated Mebendazole (methyl 5-benzoyl-2-benzimidazole-carbamate (MEB), which binds different sites on the α/β-tubulin remote from the binding sites of other MTAs, for its potential against mBC cells. MEB has much lower in vivo toxicity than the other MTAs used to treat mBC and it can be orally administrated. We explored MEB for its effectiveness in anti-mBC cells with a panel of human breast normal and mBC cell lines. The data from clonogenic survival studies indicate that MEB delivers &amp;lt; 10-fold greater cytotoxicity toward mBC cells compared to normal mammary epithelial (HME) or benign breast tumor cells. Furthermore, the cytotoxicity in detected in mBC cells was attributed to the induction of mitotic catastrophe, as demonstrated by the increased mitotic cell population (cells with 4N-DNA content and Histon-H3-Ser10 phosphorylation) and concurrent nuclear fragmentation. In contrast, under the same dose range, MEB did not cause mitotic catastrophe in HME cells. In addition, our data also show that MEB is much more efficient in killing p53-deficient mBC cells than p53-proficient mBC cells for the same reason, induction of mitotic catastrophe, which suggest the protective function of p53 against MEB-induced mitotic catastrophe. Collectively, our data support a great potential for MEB as an innovative regimen for improving mBC treatment. Citation Format: Ying Yan, Janina Baranowska-Kortylewicz, Brendan Graff. Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-01.
Abstract P3-07-02: Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer
Authors: Kristopher Lofgren, Sreeja Sreekumar, Nicolette Reker, Kyle Ernzen, Paraic A. Kenny
Journal: Cancer Research (2023)

Abstract The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we describe the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. A pan-cancer tissue microarray analysis indicates that the target is commonly detected (&amp;gt; 50% of cases) in breast, prostate, liver and lung cancer. Citation Format: Kristopher Lofgren, Sreeja Sreekumar, Nicolette Reker, Kyle Ernzen, Paraic A. Kenny. Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-02.
Abstract P5-12-06: Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients
Authors: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao
Journal: Cancer Research (2023)

Abstract Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear. Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations. Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1). Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy. Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-06.
Abstract P2-26-12: Interaction between CTCs and platelets complicate their detection by masking surface epitopes
Authors: Dorothea Schott, Monika PIZON, Katharina Pachmann
Journal: Cancer Research (2023)

Abstract 1) Background: It is well known that solid tumors have the ability to form metastases. The development of distant metastases is due to the primary tumor shedding cells that travel to distant sites via the blood vessels. Platelets specifically promote tumor cells survival in the bloodstream. To investigate the interplay between platelets and circulating tumor cells, we implemented our approach to label simultaneously circulating epithelial tumor cells and platelets. 2) Methods: 40 breast cancer patients were enrolled into the study. Blood samples were collected in EDTA tubes without fixatives and processed at 3 timepoints (0h, 24h and 48h) using the maintrac® approach. In order to visualize platelets we used anti-CD36 antibody staining. 3) Results: We observed at 0h post-blood draw platelet aggregates strictly attached to single cells that did not stain with anti-EpCAM antibody. After keeping blood samples at room temperature for 24h platelet aggregates could still be detected, but the anti-EpCAM antibody became accessible to the underlying cells. CTCs were detected in 94% of patients on day 1 post-blood draw. At 48h following initial blood drawing, platelets had almost completely disappeared from the cell surface and the number of detected CTCs remains stable between 24h and 48h. Furthermore, the number of CTCs correlates with clinical stage of disease. Patients with stage I/II have significantly less CTCs as compared to patients with stage III/IV (median 5 vs. 19 CTCs/100µl cell suspension, p&amp;lt; 0.05). 4) Conclusion: Our results suggest that platelets play a key role in masking circulating tumor cells. Masking may explain the difficulties in detection of these cells and prevention of their elimination by the immune system. Citation Format: Dorothea Schott, Monika PIZON, Katharina Pachmann. Interaction between CTCs and platelets complicate their detection by masking surface epitopes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-12.
Abstract PD2-01: Local and lymphoid immune surveillance mechanisms in “exceptional survivors” of stage 4 cancers following standard of care chemo- and targeted therapies
Authors: Helen Kakkassery, Thanussuyah Alaguthurai, Rosalind Graham, Esme Carpenter, Farhana Hossain, Sean Keane, Sheeba Irshad
Journal: Cancer Research (2023)

Abstract Breast cancer patients with advanced metastatic disease can exhibit rapid disease progression, disease stabilisation or partial responses of varying duration. However, for reasons that are not fully elucidated, a small fraction of patients will elicit an exceptional durable response to standard anticancer treatments or survive significantly longer than patients with clinically comparable tumours. Here, we investigate the drivers of immune surveillance mechanisms across breast cancer subtypes in stage IV exceptional survivors (n=13) with matched control cohorts of stage IV typical responders (n=6), early breast cancer patients (n=5) and healthy volunteers (n=17). Peripheral blood mononuclear cells (PBMCs) from patients were stained with 8 panels providing 241 non-redundant immune parameters for flow cytometry analysis. Principle Component Analysis (PCA) showed distinct segregation of the exceptional survivors from the other control groups with an immune signature in exceptional survivors constituting of activated NK, CD8 T cells and gamma delta (gd) T cells pointing towards higher innate immunogenicity in these individuals. Specifically, although these metastatic exceptional responder patients possessed comparable NK cell frequencies, the proportion of NKG2D+CD56dimCD16+ NK cells were significantly enriched compared to the typical responders. Additionally, proportions of CD8+ central memory (CD45RA- CD27+) and effector memory (CD45RA- CD27-) gd T cells, were also seen to be significantly increased. Functional in vitro validation of these findings along with scRNA sequencing of lymph node and tumour tissue is currently underway. To our knowledge, this work is the first to explore in depth the immune signatures in the peripheral blood of exceptional survivors with metastatic breast cancer. Elucidating the immunological reasons for favourable atypical responses alongside functional tumour microenvironment analysis offers unique insights for predictive biomarker identification and discovery of axes that could be exploited therapeutically to benefit those with less favourable responses. Written informed consent was obtained from all individuals in accordance with the Declaration of Helsinki under the following research ethics committee; London-Chelsea approved study (REC ID 13/LO/1248). Citation Format: Helen Kakkassery, Thanussuyah Alaguthurai, Rosalind Graham, Esme Carpenter, Farhana Hossain, Sean Keane, Sheeba Irshad. Local and lymphoid immune surveillance mechanisms in “exceptional survivors” of stage 4 cancers following standard of care chemo- and targeted therapies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-01.
Abstract PD8-05: Effectiveness of Electroacupuncture Versus Auricular Acupuncture in Reducing Pain and Improving Quality of Life in Breast Cancer Survivors with Chronic Musculoskeletal Pain
Authors: Ting Bao, W. Iris Zhi, Raymond Baser, Qing Li, Jun Mao
Journal: Cancer Research (2023)

Abstract Introduction: Chronic musculoskeletal pain is common and debilitating among breast cancer survivors. Recently, the Personalized Electroacupuncture (EA) versus Auricular Acupuncture (AA) Comparative Effectiveness (PEACE) trial demonstrated that both acupuncture methods reduced pain more than usual care (UC) in cancer survivors. However, the comparative effectiveness between EA and AA among breast cancer survivors is unknown. Here, we report the results of subgroup analysis of breast cancer survivors enrolled in the PEACE trial. Methods: PEACE is a three-arm, parallel, single center randomized trial investigating the effectiveness of EA and AA versus UC for chronic musculoskeletal pain in 360 cancer survivors. Patients in both EA and AA received ten weekly treatments. Patients in UC could receive ten EA treatments after week 12. The primary endpoint was the change in mean Brief Pain Inventory (BPI) pain intensity from baseline to week 12; change from baseline to week 24 and change in quality of life were secondary endpoints. We analyzed the subset of 46% of trial participants with a primary diagnosis of breast cancer. We conducted constrained linear mixed model analyses, which constrained all arms to have a common pre-randomization baseline mean. Model-based mean estimates at weeks 12 and 24 were compared between arms using model contrasts. Results: Among 165 breast cancer survivors, the baseline mean pain severity was 5.35 (95% Confidence Interval [CI]: 5.04, 5.66). At week 12, the BPI pain severity score was 2.69 (2.26. 3.13) in EA, 3.60 (3.17, 4.02) in AA, and 5.06 (4.47, 5.65) in UC. At week 24, the mean BPI pain severity was 2.84 (95% CI: 2.40, 3.28) in EA and 3.67 (95% CI: 3.23, 4.10) in AA. EA reduced pain severity significantly more than AA at both week 12, (-0.90 [-1.45, -0.36], p=0.001) and week 24 (-0.82, [-1.38, -0.27], p=0.004). There were no differences between EA and AA in improvements in PROMIS physical health or mental health component scores, but both EA and AA significantly improved both PROMIS scores at week 12 compared to UC. Mild toxicities were reported, more patients dropped out of the AA arm due to ear pain. Conclusions: EA was more effective than AA at reducing pain severity, but both similarly improved physical and mental health scores. Breast cancer survivors with chronic musculoskeletal pain may consider EA before AA. Citation Format: Ting Bao, W. Iris Zhi, Raymond Baser, Qing Li, Jun Mao. Effectiveness of Electroacupuncture Versus Auricular Acupuncture in Reducing Pain and Improving Quality of Life in Breast Cancer Survivors with Chronic Musculoskeletal Pain [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-05.
Abstract P5-11-04: Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC
Authors: Michal Mego, Dominik Hadzega, Gabriel Minarik, Andrea Soltysova, Petra Nemcova, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Daniel Pindak, Lubos Klucar
Journal: Cancer Research (2023)

Abstract Background: Circulating tumor cells (CTC) with phenotype of epithelial-mesenchymal transition (CTC_EMT) represent novel subpopulation of CTC associated with inferior outcome in primary breast cancer (PBC). However, molecular characterization of primary tumors associated with this CTC subpopulation is lacking. The aim of this study was to identify signaling pathways associated with presence of CTC_EMT in PBC patients using a comprehensive genomics approach. Methods: This translational study included 17 patients with PBC and 5 donors of normal breast tissue. CTC_EMT were detected before surgery by quantitative RT-PCR assay for expression of epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted, in parallel, from fresh frozen primary tumor and whole-trancriptome profiles were obtained using RNA sequencing and additionally mRNAs profiles by microarray. Genes expressions were further validated by qRT-PCR. Results: Analyzing RNA sequencing and microarray data, we found set of genes differentially expressed in absence or presence of CTC_EMT in PBC. We identified 157 genes differentially expressed in CTC_EMT phenotype compared to patients with non-detectable CTC. Namely, keratin family is represented by genes KRT5, KRT14, KRT17. Gene ontologies related to membrane structure or communication and immunology appears to be involved in CTC-related processes, pathways related to cell junction and various signaling pathways including PI3K and Ras-signaling appear to be significant in processes leading to CTC EMT presence. Conclusions: We suspect multiple genes of having a role in primary tumour processes leading to CTC EMT production in breast cancer patients. Data suggest, that PI3K &amp; Ras-signalling and pathways related to cell junction are the key pathways for changes inside of primary tumour tissue between CTC EMT and CTC- phenotype of breast cancer patients. We propose, additional study with single-cell resolution is needed for better understanding of the processes. Citation Format: Michal Mego, Dominik Hadzega, Gabriel Minarik, Andrea Soltysova, Petra Nemcova, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Daniel Pindak, Lubos Klucar. Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-11-04.